Sinus arrhythmia caused by pemetrexed with carboplatin combination: A case report

Combination chemotherapy of pemetrexed and carboplatin is a standard treatment approach for non-small cell lung cancer (NSCLC). However, no prior reports have described cardiotoxicity associated with this therapeutic combination or sinus arrhythmia in oncological contexts. Here, we report the case of a 44-year-old female NSCLC patient that suffered from sinus arrhythmia following combined chemotherapeutic treatment with pemetrexed and carboplatin. The patient was successfully treated under medical guidance, and the condition was effectively reversed following the discontinuation of this chemotherapeutic regimen and medication prescribing. Overall, this represents a rare case of sinus arrhythmia in NSCLC patient during the first cycle of combined chemotherapy with pemetrexed and carboplatin. However, a putative etiological basis for this rare clinical entity remains to be established.


Introduction
As a basic folate antagonist and antineoplastic agent, pemetrexed is primarily used to treat advanced non-small cell lung cancer (NSCLC) [1]. It alleviates rate-limiting enzyme activity in the folate-dependent metabolic pathway, inhibiting pyrimidine and purine biosynthesis from suppressing tumor cell proliferation [2]. Carboplatin is an intravenously administered platinum coordination complex and alkylating agent administered as a chemotherapeutic drug to treat lung cancer patients [3]. In many cases, pemetrexed and carboplatin are ideal for the chemotherapeutic treatment of NSCLC as they exhibit limited toxicity and significant chemotherapeutic efficacy [4]. However, herein we report the case of a patient who experienced sinus arrhythmia due to the combination therapy of pemetrexed and carboplatin.

Chief complaints
The 44-year-old female patient experienced paroxysmal palpitations without chest tightness and chest pain on the day of combined chemotherapeutic treatment with pemetrexed and carboplatin.

History of present illness
The patient received three cycles of combined chemotherapy of carboplatin and pemetrexed from August to October 2019; however, in the fourth cycle of chemotherapy, that is, around January 2020, the patient developed cardiotoxicity. In particular, the patient suffered from sinus arrhythmia 8 h after the combined infusion of pemetrexed (800 mg q.d.) and carboplatin (450 mg q.d.).

History of past illness
The patient had no history of diabetes, hypertension, mental illness, or cardiovascular/cerebrovascular disease and did not receive any daily pharmacological treatment. However, the patient had been diagnosed with stage IV (cT4N1M1a) NSCLC, for that adenocarcinoma subtypes were identified since November 2011. Secondary malignant tumors in the bone and liver were also confirmed in this patient. Her medical schedule from 2012-2020 is detailed in Table 1.

Physical examination upon admission
An initial evaluation of the patient suggested her being underweight, with a body mass index (BMI) of 18.96 kg/m 2 , a temperature of 36.5 C, blood pressure of 120/74 mmHg, and a heart rate of 121 bpm.

Laboratory investigations
Initial evaluations of patient electrolyte levels are illustrated in Supplementary Table 1. The complete blood count parameters do not show any abnormalities (Supplementary Table 1), while serum thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH), free T3 (FT3), and free T4 (FT4) levels were not assessed.

Imaging examinations
In light of the patient's high heart rate (121 bpm), she was assessed with a point-of-care electrocardiogram (ECG) monitoring within the first 12 h following presentation, revealing sinus tachycardia and marked sinus arrhythmia. Serum TroponinT (TnT), brain natriuretic peptide (BNP), creatine kinase isoenzyme (CKMB), and myoglobin (Myo) levels were analyzed, and no anomalies were found (Supplementary Table 2). Dynamic ECG results suggested frequent atrial premature beats and short-array chamber tachycardia. Ultrasound cardiogram (UCG) results were consistent with heart valve degeneration, aortic regurgitation, mitral regurgitation, tricuspid regurgitation, and impaired left ventricular diastolic function ( Figure 1). Cardiologists were invited for consultation, and mild cardiotoxicity was specified for this patient.

Treatment
Due to the immediate onset of cardiotoxicity followed by chemotherapeutic treatment, the next dose of these chemotherapeutic drugs was suspended. Cardioprotective treatment was immediately initiated by administering Metoprolol Tartrate Tablets (12.5 mg b. i.d.). The patients presenting symptoms were alleviated after two days since such medication was initiated. However, she still experienced occasional palpitations, and dynamic ECG monitoring revealed paroxysmal sinus tachycardia and frequent atrial premature beats. Consequently, Metoprolol Succinate Sustained-Release Tablets (47.5 mg q. d.) were administered for six days. The patient underwent regular ECG and UCG follow-up monitoring daily after sinus arrhythmia.

Outcomes and follow-up
The patient exhibited occasional palpitations that disappeared after six days of the treatment of Metoprolol Succinate Sustained-Release Tablets, with ECG monitoring results returning to normal ( Figure 2). Moreover, the chemotherapy with pemetrexed and carboplatin was suspended. The patient underwent intravenous infusion treatment with zoledronic acid (4 mg q.d.) and orally ametinib (110 mg q.d.).

Causality assessment
Naranjo adverse drug reaction algorithm was carried out to assess imputability resulting in a "probable" association [5]. Naranjo nomogram questionnaire yielded a score of 5, which contained the first evidence of a sinus arrhythmia induced by the combination of pemetrexed and carboplatin (Table 2).

Discussion
Cardiotoxicity rates range from 0.06% to 1.14% in patients undergoing antineoplastic drug treatment, with these adverse events primarily depending on the selected chemotherapeutic regimen, cardiac status, and drug dosage [6,7]. 5-Fluorouracil (5-FU) and its precursor capecitabine have been reported to cause cardiotoxicity, presenting in the form of myocardial ischemia, arrhythmia, congestive heart failure, cardiogenic shock, and even sudden death [8]. However, such cardiotoxicity has primarily been attributed to frequent treatment and cumulative 5-FU administration [9]. Paclitaxel and carboplatin chemotherapy could induce abnormal ECG in ovarian cancer patients with either normal or abnormal prior ECG, but its consequence was of no clinical significance [10]. Nedaplatin-induced cardiotoxicity is also rare, although it has been presented that three patients treated with nedaplatin develop chemotherapy-induced serious arrhythmias [11]. In addition, few  cardiac adverse effects have been observed on tyrosine kinase inhibitors (TKIs), although long-term erlotinib maintenance may have transformed minimal cardiotoxicity into dilated cardiomyopathy [12]. Pemetrexed is primarily metabolized in its original form and eliminated in the urine, causing limited damage to the renal system, peripheral nervous system, skin, and bone marrow [13]. However, there have been reports of pemetrexed-induced sweet syndrome and edema of the eyelids and scalp [14,15]. Carboplatin is generally characterized as a relatively "gentle" chemotherapeutic drug, exhibiting limited hematopoietic toxicity [16]. Currently, no relevant evidence is available in findings about the cardiotoxicity induced by pemetrexed. Moreover, cardiotoxicity is not listed as a common side effect of platinum-based drugs, although the number of clinical cases reporting cardiotoxic events occurring during or shortly after cisplatin infusion has increased [17]. Most importantly, no patient-reported cardiotoxicity following the combination of pemetrexed and carboplatin was referred in clinical trials. The toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin, including neutropenia, anemia, myelosuppression and thrombocytopenia. Non-hematological adverse events such as febrile neutropenia, appetite loss, nausea, and bacterial pneumonia were rare [18,19,20,21,22,23]. Here, we report a novel case in which pemetrexed and carboplatin appear to have triggered sinus arrhythmia in a patient undergoing multiple courses of chemotherapy. However, it is difficult to make any definitive statements regarding the mechanisms underlying this case of sinus arrhythmia, given published evidence regarding the combination of pemetrexed and carboplatin treatment.
It has been hypothesized that cisplatin's cardiotoxicity occurs due to electrolyte imbalance or disturbance of the SA node [24]. Cisplatin is also speculated to direct ROS attacks on vascular endothelium, inducing platelet activation and aggregation to promote thrombosis [25]. Prior studies have reported sporadic instances of cardiotoxicity associated with antineoplastic drugs likely arising due to the induction of ischemia as a consequence of coronary artery spasms [26]. Herein, it is important to note that the patient did not exhibit sustained cardiotoxicity during the early stages of pemetrexed and carboplatin treatment, suggesting that the cumulative accumulation of these chemotherapeutic drugs for prolonged chemotherapeutic treatment is likely to have contributed to the development of sinus arrhythmia. UCG examination of the patient in the present report revealed evidence of heart valve degeneration, aortic regurgitation, mitral regurgitation, tricuspid regurgitation, and impaired left ventricular diastolic function. However, ECG results did not reveal the presence of any cardiovascular dysfunction before initiating the pem-carbo chemotherapy ( Figure 3). Thus, it can be inferred that the accumulation of the selected chemotherapeutic drugs contributed to myocardial ischemia and sinus arrhythmia with concomitant impairments in cardiac energy metabolism, blood perfusion abnormalities, and oxygen deficiency. Secondary thrombosis due to damage to myocardial cells and the vascular endothelium may have occurred following chemotherapeutic treatment, contributing to  sinus arrhythmia. Additionally, it is important to consider that multiple factors, including cumulative chemotherapeutic drug accumulation, the selective cardiotoxicity of this chemotherapeutic regimen, aging, and heart disease-related risk factors, are likely to have all contributed to this case of sinus arrhythmia induced by the combination of pemetrexed and carboplatin.
To the best of our knowledge, this is the first published evidence suggesting that the combination of pemetrexed and carboplatin can induce cardiotoxicity. The present report of sinus arrhythmia in a patient undergoing combined pemetrexed and carboplatin treatment thus offers potentially new insight into the risk profile associated with this treatment regimen. However, it remains challenging to determine whether and how underlying cardiotoxicity in an otherwise asymptomatic patient was reinforced or exacerbated by these chemotherapeutic drugs. Further research exploring the mechanisms triggering sinus arrhythmia in patients undergoing combination pemetrexed and carboplatin-based chemotherapy is thus warranted to elucidate the targeted solutions for these rare cases, even though the present patient exhibited an excellent outcome.

Author contribution statement
All authors listed have significantly contributed to the investigation, development and writing of this article.

Funding statement
This work was supported by the National Natural Science Foundation of China (82204433), the Natural Science Foundation of Shandong Note: The probability that an adverse event is related to drug therapy was confirmed based on indicated questionnairea using the Naranjo criteria. A list of weighted questions such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose-response relationships and previous patient experience with the medication should be identified. The ADR is assigned to a probability category from the total score as follows:total score: >9 (Definite), 5-8 (Probable), 0-4 (Possible), and <0 (Doubtful). DNK: Do Not Know. Province, China (ZR2020QH362), and the clinical medicine Xþ project of the affiliated hospital of Qingdao University.

Data availability statement
Data included in article/supp. material/referenced in article.

Declaration of interest's statement
The authors declare no conflict of interest.

Additional information
Supplementary content related to this article has been published online at https://doi.org/10.1016/j.heliyon.2022.e11006.

Patient consent
Informed consent was obtained from the patient.